Three-month treatment outcome of medication-overuse headache according to classes of overused medications, use of acute medications, and preventive treatments

Medication overuse headache (MOH) is a chronic headache disorder that results from excessive use of acutely symptomatic headache medications, leading to more frequent and severe headaches. This study aims to assess the 3-month treatment outcomes in MOH patients, focusing on the types and usage of overused medications, as well as preventive treatments. This prospective cross-sectional study analyzed the treatment outcomes of 309 MOH patients from April 2020 to March 2022. Patients were advised to discontinue overused medications immediately and offered preventive treatments based on clinical judgment. Data on headache characteristics, medication use, and impact on daily life were collected at baseline and 3 months. Results showed overall significant improvements in headache-related variables in patients completing the 3-month treatment follow-up. The median number of headache days per month decreased from 15 days at baseline to 8 days after 3 months (p < 0.001). Patients who overused multiple drug classes demonstrated increased disability levels (mean Headache Impact Test-6 score: 62 at baseline vs. 56 at 3 months, p < 0.01). Those who continued overusing medications reported more days of severe headache (mean 18 days at baseline vs. 14 days at 3 months, p < 0.05) and greater impact (mean Migraine Disability Assessment score: 35 at baseline vs. 28 after 3 months, p < 0.05) compared to the baseline. Differences in headache outcomes were evident across different preventive treatment groups, with generalized estimating equation analyses highlighting significant associations between clinical characteristics, overused medication classes, and preventive treatments. Most MOH clinical features significantly improved after 3 months of treatment. However, notable interactions were observed with certain clinical presentations, suggesting possible influences of overused medication classes, usage patterns, and preventive treatment types on MOH treatment outcomes. This study underscores the importance of individualized treatment strategies and the potential benefits of discontinuing overused medications.


Ethic approval and patient consent
This study was reviewed and approved by the Institutional Review Board of each participating center, including the Jeonbuk National University Hospital (IRB 2020-06-028-003).The study was conducted in accordance with the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines 21 .The patients provided written informed consent prior to participation.All methods were carried out in accordance with relevant guidelines and regulations including the Declaration of Helsinki and its following amendments.

Statistical analysis
This descriptive prospective observational study included patients with MOH referred to headache centers in South Korea as a part of the RELEASE study.This study was a secondary analysis of the RELEASE data.The RELEASE study aimed to enroll a minimum of 341 patients, based on a rationale described previously.As an observational study, this analysis did not have a predefined sample size based on statistical power calculations.The hypothesis testing was conducted using a two-tailed approach to assess potential differences in the 3-month treatment outcomes of MOH patients based on the classes and usage of overused medications and types of preventive treatments.This approach allows for the consideration of both increases and decreases in treatment outcomes associated with varying factors.The Kolmogorov-Smirnov test was used to assess variable distribution normality.For non-normally distributed variables, we used the Wilcoxon signed-rank test to compare the baseline and 3-month follow-up data for each overuse group.Pearson's chi-square test was performed for categorical variables.For our non-normally distributed longitudinal data, we adopted the Generalized Estimating Equation (GEE) method to evaluate the influence of variables such as classes and use of overused medications and preventive treatments, adjusting for patient baseline variables including age, sex, anxiety, and depression 22 .We also calculated means, standard deviations, and 95% confidence intervals for outcomes using GEE with posthoc analysis.Differences in clinical characteristics according to the classes and use of overused medications and preventive treatments after the 3-month treatment were analyzed using GEE with post hoc analysis.GEE statistical analysis is useful when dealing with related or repeated measurements in data 23 .It's handy for studies with multiple observations for the same individuals or when considering correlations between groups 24 .GEE takes into account the correlation structure of the data, making it robust to outliers and non-normal distributions.It's also effective for handling clustered or panel data 23,24 .GEE tends to provide more accurate and efficient results compared to traditional linear models 24 .Multicollinearity was assessed using the variance inflation factor (VIF), which was significant with VIF > 10 and no multicollinearity.Non-repeated measures involving non-normally distributed variables were compared using the Kruskal-Wallis test, followed by post hoc pairwise comparisons with a Bonferroni-corrected Mann-Whitney U test.Data are presented as a median with an interquartile range, with a two-tailed p-value < 0.05 considered statistically significant.All analyses were performed using SPSS software version 22 (IBM, Armonk, NY, USA).
Table 1 shows a comparative analysis of baseline variables in MOH patients by classes and use of overused medications, and preventive treatment.The sex distribution was consistent across the five groups of overused medications, three groups of use of overused medications, and five preventive treatment groups.However, the age distribution varied according to the medication class.The T-MOH group had fewer monthly headache days, severe headache days, days with acute medications, and pharmacy visits, along with more crystal-clear days at baseline.When evaluated according to the types of preventive treatment, the no-preventive treatment group had more crystal-clear days and fewer headache days those using preventive treatments.Likewise, the oral medication-only and no-treatment groups exhibited lower MIDAS scores but higher MSQ scores and headache-related clinical measures than the OBT-A and anti-CGRP mAb groups.In contrast, the OBT-A, anti-CGRP mAb, and combination treatment groups exhibited more severe clinical profiles and had fewer clear crystal days and more headache days than the no-treatment and oral medication-only groups.These results suggest that patients with more severe symptoms are more likely to use preventive treatment other than oral medications.

Baseline vs. 3-month follow-up variables by classes of overused medications
M-MOH was the most common form of MOH, accounting for 25.6% (79/309) of all patients.Among MOH groups that overused a single medication, N-MOH was the most common, at 23.9% (74/309), whereas O-MOH was the rarest, at 1.3% (4/309) (Table 2).A GEE analysis, incorporating covariates including age, headache duration, CDH duration, and baseline monthly metrics such as crystal-clear days, headache days, and severe headache days, was conducted to assess the impact of classes of overused medications and the timing of visits (baseline vs. 3-month) on the clinical features of participants with MOH.Significant improvements were observed in all clinical parameters at the 3-month follow-up compared with those at baseline (Table 2).At the 3-month mark, the GEE model showed that patients in the M-MOH group had notably higher pharmacy visit days and HIT-6 and MIDAS scores than those in the T-MOH (p = 0.009), C-MOH (p = 0.003), and N-MOH (p = 0.04) groups, respectively.Additionally, the N-MOH group exhibited significantly lower MIDAS scores than the T-MOH (p = 0.025) and C-MOH (p = 0.001) groups.Except for the crystal-clear days per month (p = 0.018) and MIDAS scores (p = 0.018), no significant interaction was observed between the classes of overused medication and visits (Table 2).In essence, this suggests that the change in the crystal-clear days per month and MIDAS scores over time may differ depending on the type of medication.
Regarding the impact of headache, the discontinuation group had lower HIT-6 scores than the maintenance (p = 0.002) and reduction (p = 0.001) groups.Furthermore, the discontinuation (p = 0.001) and reduction (p = 0.019) groups had higher MSQ scores than the maintenance group (Table 3).
Regarding the interaction between visits and the use of overused medications, GEE analysis showed significant interactions for the following parameters: change in crystal-clear days per month, monthly pharmacy visits, and HIT-6, PHQ-9, and MSQ scores.This implies that the clinical outcomes at the 3-month follow-up were influenced by the use of overused medications in relation to the timing of the visit (Table 3).

Baseline vs. 3-month follow-up variables by types of preventive treatments
During the 3-month follow-up period of the 309 participants, 21 declined preventive treatment, leaving 288 participants who received preventive interventions (Table 4).None of the participants switched their initial treatment plan during the entire 3-month study period.The oral medication-only group was the most common, encompassing 149 (51.7%) participants, followed by the OBT-A group with 59 (20.5%) participants and anti-CGRP mAb group with 53 (18.4%) participants.A smaller cohort of 27 participants (9.4%) received a combination of the OBT-A and anti-CGRP mAb.All participants in the OBT-A and anti-CGRP mAb groups were administered oral preventive medications.
After 3-month of treatment, the no-treatment group showed significantly fewer headache days per month than the other treatment groups.The oral medication-only group experienced fewer severe headache days per month and had lower HIT-6 scores than the OBT-A group.Notably, the anti-CGRP mAb group had a higher MSQ score than the other treatment groups (Table 4).Subsequent GEE analysis showed a significant interaction between the types of preventive treatments and changes in clinical characteristics such as headache days per month, severe headache days per month, hospital visits per month, missed days per month, and MSQ scores, suggesting that the variability in these outcomes over time may be influenced by the type of preventive treatments (Table 4).

Discussion
The main findings of this 3-month prospective observational study are as follows: (1) A significant improvement in MOH was observed at the 3-month follow-up from baseline.This improvement was consistent regardless of the classes and use of overused medications and types of preventive treatments.(2) Some clinical characteristics at 3 months including headache and severe headache days per month, pharmacy visits per month, as well as HIT-6, MIDAS, and MSQ scores, exhibited significant differences according to the classes and use of overused medications and types of preventive treatments.(3) The classes and use of overused medications and types of preventive treatment showed significant interactions with some clinical characteristics of MOH at the 3-month mark.Specifically, patients overusing multiple drug classes experienced a higher impact of headaches than those overusing combined analgesics at baseline and 3 months.Furthermore, some clinical features of patients who maintained their use of overused acute medications were more severe than those of patients who either discontinued or reduced their use of overused acute medications after the 3-month period.
MOH is a serious condition that imposes approximately 3 times the burden on individuals as migraine and approximately 10 times the burden of tension-type headaches 10,25 .Given that adequate MOH treatment provides significant benefits to individuals and society, healthcare systems should prioritize the treatment of MOH 26 .The present study validated previous reports that MOH treatment significantly improved patients' disability and quality of life and clinical characteristics of headaches, regardless of the classes of overused medications 27,28 .Our results further support the urgent need for the diagnosis and treatment of MOH from the patient's perspective.
Notably, our results showed that patients with M-MOH had more profound disabilities and a higher impact of headache than patients who overused single-class medications at the 3-month follow-up.In our previous study, the M-MOH group displayed more severe clinical characteristics than the single-class MOH groups 14 .Considering these, multidrug overuse negatively influences not only MOH clinical presentations at baseline but also patient prognoses; however, the underlying mechanisms of this difference remain elusive 29 .Nevertheless, the ongoing interplay of multiple drug classes might impact multiple pathways, reducing the threshold for headache expression and leading to the development of more severe forms of headache.Our previous research indicated a faster transition from CDH onset to MOH in the M-MOH group compared to single-class MOH groups 14 .This accelerated progression implies that the M-MOH not only exacerbates symptoms but is also linked to a higher risk of headache chronification and shortens the time needed for MOH development.
Despite the high prevalence of MOH, a universally accepted treatment strategy has yet to be established 1,8 .Attempts to create an internationally recognized evidence-based guideline are ongoing; however, inconsistencies persist in various aspects of MOH treatment, leading to significant differences in therapeutic approaches 30,31  www.nature.com/scientificreports/One of the major debates is the use of overused medications 8,32 .Withdrawal treatment can transform a chronic headache back into an episodic form in roughly 70% of patients 33,34 .A study by the Danish Headache Center demonstrated that a 2-month outpatient detoxification program, which did not permit the use of any acute migraine medication for breakthrough pain, was more successful than allowing limited use of acute migraine medication with a maximum of 2 days per week 35 .A study that compared three MOH treatment strategiessimultaneous withdrawal and preventive treatment, preventive treatment without withdrawal, and withdrawal with the possibility of delayed preventive treatment-demonstrated that all strategies were effective in managing MOH.However, the combination of withdrawal and preventive treatment was more effective than preventive treatment alone 35 .The present study highlighted that patients who maintained their use of overused acute medications had less favorable outcomes than those who discontinued or reduced their use of overused acute medications.This finding implies that stopping or reducing the use of overused medications could be more beneficial than maintaining medication use for the treatment of MOH.
In recent decades, significant advances have been made in preventive treatments for patients with MOH.In recent randomized controlled trials, OBT-A and monoclonal antibodies targeting CGRP or its receptor have been shown to be effective in the treatment of MOH 36,37 .The present study showed that patients with severe clinical profiles were more likely to opt for OBT-A and anti-CGRP mAbs, in addition to oral preventive treatment.Table 2. Evaluation of baseline and 3-month follow-up parameters in MOH patients based on classes of overused medications.Data are presented as a median (25-75th percentiles).Data from four patients with opioid-overuse headaches are not presented in the table.p value from generalized estimating equation method between groups, with age, headache duration, CDH duration, CDH to MOH period, and baseline of CCD, MHD, SHD, AMD, monthly pharmacy visits and the initial values of each scale before treatment as a covariate.*p value for visit main effect.† p value for class of medication main effect.‡ p value for visit x medication (interaction) effect.CDH: chronic daily headache; C-MOH: combination analgesic-overuse MOH; E-MOH: ergotamine-overuse MOH; GAD-7: general anxiety disorder-7; HIT-6: headache impact test-6; MIDAS: migraine disability assessment; M-MOH: MOH attributed to multiple drug classes; MOH: medication-overuse headache; MSQ: migraine-specific quality of life questionnaire; N-MOH: non-steroidal anti-inflammatory drug-overuse MOH; PHQ-9: patients health questionaire-9; T-MOH: triptan-overuse MOH.Significant values are in bold.weakening the analysis.This could explain the absence of significant results in certain subgroup analyses.Fourth, the follow-up period of the present study was relatively short.Many follow-up studies of MOH had a 6-month to 1-year follow-up period, whereas our study had a follow-up period of only 3 months.However, a study conducted in seven European and South American countries found significant improvements in monthly headache days and comorbid anxiety and depression after three months of initiating MOH treatment.Nonetheless, there was no significant change in symptoms were noted after that.In a randomized controlled trial comparing preventive treatment and withdrawal of overused medications of MOH, the number of monthly migraine days, days with acute medications and pain intensity improved significantly after 2-month treatment, with no further difference at 6-month.Therefore, even with a 3-month follow-up period, our study should be able to capture most of the changes after MOH treatment.Finally, the inclusion of patients solely from seven specialized referral hospitals in a designated area might skew the representation, possibly resulting in a selection bias towards patients with more severe headaches compared to those attending primary clinics.

Variables
In conclusion, this prospective registry study found a significant improvement in MOH after a 3-month treatment from the baseline.Nevertheless, some clinical characteristics of MOH significantly differed according to the classes and use of overused medications and types of preventive treatments at 3 months.GEE analyses revealed significant interactions between the classes and use of overused medications and types of preventive treatment and some clinical characteristics at the 3-month mark, suggesting that the clinical outcomes of MOH treatment may be influenced by overused medications, use of overused medications, and types of preventive treatment.

Table 1 .
Comparative analysis of baseline variables in MOH patients by classes and use of overused medication and preventive treatment types.Kruskal-Wallis test and Mann-Whitney U test as post hoc test, data are presented as n (%) and a median (25-75th percentiles), and data from four patients with opioid-overuse headaches are not presented in the table.Anti-CGRP mAb: anti-Calcitonin Gene-Related Peptide monoclonal antibody; CCD: crystal-clear days; C-MOH: combination analgesic-overuse MOH; DAM: days with acute medications per month; E-MOH: ergotamine-overuse MOH; GAD-7: general anxiety disorder-7; HD: headache days; HIT-6: headache impact test-6; HV: hospital visits per month; MD: Missed days; MIDAS: migraine disability assessment; M-MOH: MOH attributed to multiple drug classes; MOH: medication-overuse headache; MSQ: migraine-specific quality of life questionnaire; N-MOH: non-steroidal anti-inflammatory drug-overuse MOH; PHQ-9: patients health questionaire-9; OBT-A: OnabotulinumtoxinA; PV: Pharmacy visits per month; RD: reduction per month; SHD: severe headache days per month; T-MOH: triptan-overuse MOH.Significant values are in bold.